The peptides of human parathyroid hormone (to be referred to as “hPTH” hereinafter) are biologically active peptides which are responsible for bone metabolism, and have an strong activity to develop bones (Aurbach et al., Recent Progr. Horm. Res., 1972, vol. 28, p. 35). The hPTH is a peptide typically composed of 84 amino acid residues (hPTH(1-84)). A derivative, hPTH(1-34), from hPTH(1-84) composed of 34 amino acid residues designated as amino acid Nos. 1-34 of hPTH(1-84) has been also known to have the same pharmacological activity as does hPTH(1-84) (Tregear et al., Hoppe-Seyler's Z. Physiol. Chem., 1974, vol. 355, p. 415). The amino acid sequences of hPTH(1-84) and hPTH(1-34) are given as Sequence Nos. 1 and 2 in the Sequence Listing, respectively.
Calcitonin and bisphosphonate or therapeutic agents used for the treatment of osteoporosis exhibit their therapeutic effects by inhibiting bone resorption, whereas hPTH(1-84) and hPTH(1-34) stimulate bone formation, or bone metabolism involved in the bone formation. Thus, those peptides have been expected to serve as a new therapeutic agent of osteoporosis (Lane et al., J. Clin. Invest., 1998, vol. 102, pp. 1627–1633).
It has been reported, when hPTH(1-34) is subcutaneously applied to humans at a certain dose once weekly, it will increase the bone mineral content, while, when the same agent is similarly applied at a dose one fifth the previous one but once daily for five days successively, it will also increase the bone of mineral density (BMD) significantly (Sone et al., Miner Electrolyte Metab., 1995, vol. 21, pp. 232–235). In animal experiments it has been shown that hPTH, when given subcutaneously at a certain dose once weekly, will cause less BMP to bones than is observed when it is given divisional (Tawaragi et al., Osteoporosis International, vol. 6, suppl. 1, 1996, p. 245). This suggests a maximum therapeutic effect from hPTH will be obtained when hPTH is given daily at a small dose over a long period than when it is given at a large dose for a short period with a long interval between successive doses. If a small dose of hPTH given continuously over a long period will ensure an therapeutic effect equal to or more excellent than does a large dose given intermittently for a short period, this prescription will be also desirable from the view-point of small doses of hPTH being probably free from the adverse effects on the digestive and cardiovascular organs which are known for high dose administrations of hPTH.
Also, injections would be unsuitable to be used for the treatment of the patient with osteoporosis who will usually require a long term treatment, because the patient should then receive the treatment under the management of a physician; feel a more or less pain during treatment; and visit the physician's office regularly for treatment which would be a burden to the patient.
In view of this, there is a need for a nasal drug which would allow the patient to easily take it at home daily over a long period with no undue pain and burden imposed upon the patient.
However, for a nasal drug to be safely used continuously over a long period it is absolutely necessary that the drug should be smoothly absorbed through the nasal mucosa; have no irritating action against the nasal mucosa; and give an excellent use feeling, because the nasal mucosa is very sensitive to the irritating action of a medicine or an additive thereof. Particularly, for such a drug as the one prepared from hPTH which is expected to give a therapeutic effect when used over a long period, an excellent use feeling is very important when it is intended to be used for intranasal administration. In order to prepare a nasal drug which is acceptable even when used continuously over a long period, it is important to select the active agent in the form of a medicament or of its salt, and proper additives, to determine their effective concentrations, and to optimize their combination. The factors responsible for the use feeling of a nasal drug involve the odor and irritating activity of the drug. Thus, the kinds of medicaments or additives used for a nasal drug and their concentrations are very limited.
There is a commercially available product prepared from hPTH, that is, an injection containing a 5-acetate of hPTH(1-34) which is used as a diagnostic agent for assaying the functional activity of parathyroid (whose generic name is teriparatide acetate and which is provided by Asahi Kasei Kogyo Corp.). However, no intranasal drug based on hPTH is available that will give a satisfactory use feeling in terms of odor and irritability.
Japanese Patent Laid-Open No. 64-16799 describes that, when hPTH(1-34) is purified, it is mixed with acetic acid which is used for the purification process, and the acetic acid content in individual products vary widely from lot to lot, making it difficult to obtain products containing a uniform amount of acetic acid, and that introduction of acetic acid to the product will lead to a reduced activity of the product.
The same document further discloses a method suitable for improving the stability of hPTH(1-34) wherein a lyophilized composition of hPTH(1-34) based on the use of tartaric acid is utilized. However, tartaric acid is so highly acidic that an agent containing it will not be suitable for intranasal administration.
Japanese Patent Laid-Open No. 2-111 discloses a powdery composition for intranasal administration based on a water soluble organic acid which has been developed to improve the nasal absorption of hPTH(1-34) a biologically active peptide such as hPTH (1-34). However, the composition would not be suitable for a long term use, because it will directly irritate the nasal mucosa, depending on the kind and amount of coexistent organic acid.
As discussed above, no intranasal drug based on hPTH that is acceptable even when used over a long period, and ensures an excellent use feeling as well as good stability and absorption has been developed.